Numerous pathologies characterized by abnormal or undesirable cell death or cell growth are the result of abnormal gene expression or activity. Cellular degenerative and hyperproliferative disorders such as Alzheimer's disease and cancer are two particular examples. Although several genes that contribute to degenerative and hyperproliferative disorders have been identified, the signal transduction pathways which mediate the development of such disorders presently are not well understood.
Spinocerebellar ataxia type-2 is one example of a group of clinically similar late onset hereditary degenerative disorders affecting the brain and central nervous system. A single gene SCA2, located on chromosome 12, has been linked to development of spinocerebellar ataxia type-2; SCA2 encodes ataxin-2, a 140 kDa protein whose function is presently unknown. Clinically similar neurodegenerative disorders include, for example, spinocerebellar ataxia types 1 and 6, spinobulbar muscular atrophy, Huntington disease and Machado-Joseph disease (Trottier et al., Nature378:403-406 (1995)). Although the development of these similar disorders are mediated by distinct genes, a shared genetic alteration initiates onset of the pathologies. In the case of spinocerebellar ataxia type-2, for example, afflicted individuals exhibit expansion of a CAG trinucleotide in SCA2 and a corresponding increase in the number of glutamine residues in the encoded ataxin-2 protein (Pulst et al., Nat. Genet. 14:269-276 (1996)). Typically, afflicted individuals have a polyglutamine sequence of about 35-39 residues, whereas normal individuals have about 22 contiguous glutamine residues in ataxin-2. Similarly, CAG repeat expansion in genes linked to spinocerebellar ataxia types 1 and 6, spinobulbar muscular atrophy, Huntington's disease and Machado-Joseph disease correlate with the development of these disorders. As a result of this shared genetic alteration, these pathologies are collectively referred to as glutamine repeat disorders.
In spite of this genetic knowledge, the function of genes, such as SCA2 in general, and the role of CAG repeat expansion and corresponding glutamine sequence expansion in the development of degenerative disorders such as spinocerebellar ataxia type-2 in particular, is not understood. In this regard, the glutamine repeat sequence of SCA3 in normal individuals is in the same size range as that of the glutamine repeat sequence of SCA2 in individuals afflicted with spinocerebellar ataxia type-2. Similarly, the molecular components that regulate or mediate cellular degeneration, and the mechanism by which they participate in this signal transduction pathway, are not understood.
Thus, a need exists to identify and characterize the molecular components that participate in this signal transduction pathway, such as proteins that bind to ataxin-2 in vivo. Moreover, a need exists to identify the nucleic acid and amino acid sequences of the respective genes and gene products, their activities, and the functional domains of such binding proteins. To the extent that such molecules are identified, they can form the basis for the development of diagnostic protocols or clinical therapies useful for the diagnosis or treatment of disorders characterized by cellular degeneration or hyperproliferation. The present invention satisfies this need and provides related advantages as well.